In the United States, there are approximately 30,000 individuals who are affected by Huntington's disease (HD), a hereditary neurodegenerative disorder that is usually manifested in mid-life as a mild movement disorder. Over the next 10 to 20 years after the onset, Huntington's disease gradually progresses to a severe movement disorder, cognitive impairment and eventually death. At the molecular level, the expansion of a stretch of CAG trinucleotide repeat in the coding region of the HD gene is responsible for the disease. This expanded CAG repeat is translated to a long polyglutamine with the abnormal properties that result in cellular toxicity and aggregation and accumulation of the full-length or truncated Huntintin (HD gene protein product) containing the long polyglutamine. The long-term objectives of this application are to identify the genes and biochemical pathways that are involved in protecting the neurons against the toxic effects of long polyglutamines in Huntington's disease and at least seven other hereditary neurodegenerative disorders. To discover these genetic factors in a rapid and cost effective way, a fruit fly (Drosophila melanogaster) model of the polyglutamine aggregation and cellular toxicity was developed, and Drosophila genome was screened for genes that, when increased in levels, could suppress polyglutamine toxicity in cells. Three such genes (dmlf, dptr2, and dhdJ1) have been discovered that are homologous to the human genes for myeloid leukemia factor 1, tetratricopeptide repeat protein 2, and heat shock protein 40/HDJ1. One of the Specific Aims of this proposal is to gain insight into the mechanism of suppressor action of the proteins encoded by these three genes, by studying their tissue distribution, subcellular localization and interaction with long polygutamines by immunolabeling of tissues from the wild-type and transgenic flies. The second Specific Aim is to discover and characterize the genes responsible for suppression effects in two other fly lines by identifying the genes that are likely to be increased in levels in these flies and then testing them for suppression effect in transgenic flies. Finally, the third Specific Aim of this application is to investigate the effect of therapeutic versus prophylactic expression of these suppressor genes in curing or preventing neuronal degeneration and dysfunction and polyglutamine aggregation, by tetracycline-inducible expression of suppressor genes before or after polyglutamine expression, or onset of degeneration and dysfunction.